Production of 5, 6, 7 or 8-hydroxy-1, 2, 3, 4-tetrahydro and decahydro-isoquinolines



United States Patent Oflice 3,379,739 Patented Apr. 23, 1968 3,379,730PRODUCTION OF 5,6,7 R 8-HYDROXY-1,2,3,4-TET- RAHYDRO ANDDECAHYDRO-ISOQUINOLINES Ian William Mathison, Memphis, Tenn., assignorto Marion Laboratories, Inc., Kansas City, Mo., a corporation ofDelaware N0 Drawing. Filed July 16, 1965, Ser. No. 472,660 8 Claims.(Cl. 260-486) ABSTRACT OF THE DISCLOSURE Disclosed is the production of5,6,7 or 8-hydroxy-l,2,3, 4-tetrahydroand decahydro-isoquinolines andbenzoyl derivatives thereof. The ring nitrogen of the isoquinoline groupis unsubstituted or alkyl substituted. The compounds have biologicalactivity. Some increase arterial blood flow in animals.

This invention relates to novel chemical compounds and processes ofpreparing the same. More particularly, this invention is concerned withnovel reduction products of hydroxyisoquinolines, particularly suchproducts having biological activity, and novel chemical processes ofpreparing such reduction products.

According to one aspect of the present invention there are providednovel 5,6,7 or 8-hydroxy-2-R-l,2,3,4,-tetrahydroisoquinolines of theformula wherein R is a lower alkyl such as methyl, ethyl and propyl, andesters and salts thereof, and novel 5,6,7 or 8-hydroxy-Z-R-decahydroisoquinolines of the formula N-Ri wherein R ishydrogen or a lower alkyl such as methyl, ethyl and propyl, and estersand salts of such compounds,

as well as his ethers thereof of the formula wherein R is lower alkyland X is an anion such as the chloride or bromide ion.

The quarternrary salts of the hydroxyisoquinolines can be producedconveniently by reaction of a 5,6,7 or 8-hydroxyisoquinoline with analkyl halide. Alkyl halides such as methyl chloride, ethyl bromide andpropyl bromide may be used in the reaction. The reaction is readilyeftected by combining the hydroxyisoquinoline and alkyl halide in asuitable liquid reaction meduim such as a lower alcohol and particularlyethanol. The reaction mixture can be heated, such as at reflux, topromote the reaction. The desired product can then be recovered from thereaction mixture by conventional isolation techniques.

Reduction of the 5,6,7 or 8-hydroxy-2-lower alkyl isoquinolinium halideusing moderate catalytic hydrogenation procedures gives the desired5,6,7 or 8-hydroxy-2- lower alkyl-l,2,3,4-tetrahydroisoquinoline in theform of a hydrohalide salt which upon treatment with a base such assodium hydroxide yields the free tertiary amine.

This reduction is conveniently effected using hydrogen at a moderatelyelevated pressure, such as about 25 to p.s.i., a finely divided platinumoxide catalyst and room temperature. To facilitate the reduction theisoquinoline compound is first dispersed in a suitable organic liquidand advisably one in which the isoquinoline salt is soluble. Ethanol isa particularly suitable solvent for the halide salts. The progress ofthe reduction can be followed by the hydrogen uptake. Once thetheoretical amount of hydrogen has been consumed the reduction can beterminated, the mixture filtered and the filtrate concentrated tocrystallize the desired product as the hydrohalide salt.

Some of the 2-alkyl tetrahydroisoquinolines which may be produced asdescribed are:

S-hydroxy-Z-methyl-1,2,3,4-tetrahydroisoquinoline,S-hydroxy-Z-ethyl-l,2,3,4-tetrahydroisoquinoline,

5 -hydroxy-2-propyl-1,2,3,4-tetrahydroisoquinoline,7-hydroxy-2-ethyl-l,2,3,4-tetrahydroisoquinoline, and6-hydroxy-2-butyl-1,2,3,4-tetrahydroisoquinoline.

Although it appeared feasible to effect direct decahydrogenation of the5,6,7 or S-hydroxy-Z-lower alkyl isoquinolinium halides to produce the5,6,7 0r 8-hydroxy- 2 lower alkyl decahydroisoquinolines this reduction,which employs stringent conditions, lead to a bis-(2-lower alkyldecahydroisoquinoline) ether rather than the alcohol. This process canbe represented as follows:

wherein R is a lower alkyl and X is a halide ion, and advisably thebromide ion. This reductive condensation can be etfected in glacialacetic acid containing a small amount of a strong acid, and particularlysulfuric acid, using an Adams platinum oxide catalyst and hydrogen atabout 25 to 100 p.s.i. The hydrogenation proceeds at room temperatureand is usually completed in about 5 to 48 hours. After filtering, thefiltrate can be made alkaline and the free base extracted with ether.

Similar ethers may be produced as described in the procedure forbis-(2-ethyldecahydroisoquinoline)ether.

The free base of the ether can then be converted to an acid additionsalt such as a hydrohalide or sulfate by conventional procedures or, ifdesired, quaternary ammonium salts can be formed, such as by reactingthe free base with an alkyl halide, alkyl sulfate, aralkyl halide oraralkyl sulfate including methyl chloride, ethyl iodide, ethyl bromideand benzyl chloride.

The unexpectedness of the production of the described ethers is shown bythe application of the same process conditions to the tertiaryhydroxyisoquinolines. The tertiary amines, as the free bases, arereduced to hydroxy dechaydroisoquinolines by hydrogenation in glacialacetic acid using platinum oxide as the catalyst. The process can berepresented as follows:

/\ NII Some of the compounds which may be produced as described areS-hydroxy decahydroisoquinoline, 6-hydroxy decahydroisoquinoline and7-hydroxy decahydroisoquinoline.

In order to produce the 5,6,7 or 8-hydroxy-2-lower alkyldecahydroisoquinolines it appears necessary to first convert the 5,6,7or 8-hydroxy-2-lower alkylisoquiuolinium halide to the correspondinghydroxide and to then hydrogenate the resulting hydroxide. Production ofthe hydroxide can be readily achieved by reacting the halide with silveroxide. This reaction can be illustrated as follows:

wherein R is lower alkyl and X is a halide ion. The reaetion proceedsreadily in an aqueous lower alcohol such as 50% methanol. The desiredproduct can be isolated from the reaction mixture by conventionalprocedures. Among the compounds which may be produced in this way are-hydroxy-2-ethylisoquinolinium hydroxide, 5 -hydroxy-Z-methylisoquinolinium hydroxide, 7-hydroxy2 propylisoquinoliniumhydroxide and 8-hydroxy-2-ethylisoquinolinium hydroxide.

Conversion of the 5,6,7 or 8-hydroxy-2-lower alkyl isoquinoliniumhydroxide to the 5,6,7 or S-hydroxy-Z-lower alkyl decahydroisoquinolinecan be effected by hydrogena- .4 present on the starting material. Theprocess using the hydroxide starting material can be represented asfollows:

where R, is lower alkyl and R R and R are hydrogen, lower alkyl such asmethyl and ethyl, lower alkoxy such as methoxy and ethoxy, or a halogensuch as chlorine and bromine.

The esters may be produced by reacting the appropriate benzoyl halidewith a hydroxy-2-lower alkyl-l,2,3,4-tetrahydroisoquinoline or ahydroxy-Z-lower alkyl decahydroisoquinoline. These reactions can berepresented as follows:

tion in glacial acetic acid using a platinum oxide catalyst even thoughthe same conditions lead to the bis-ether wherein X is a reactivehalogen, particularly chlorine or bromine and R R R and R have theassigned sigwhen a halide anion, instead of the hydroxyl anion, isnificance.

The esterification is readily effected in an organic solvent underanhydrous conditions at moderately elevated temperatures and advisablyunder reflux conditions. Dry benzene and toluene are particularlysuitable reaction media. After the reaction is terminated the desiredproduct can be isolated from the reaction mixture by conventionalprocedures. Somewhat higher esterification temperatures are used toesterify the decahydro compounds because the hydroxy group on suchcompounds is less reactive than on the aromatic nucleus present in the1,2,3,4- tetrahydroisoquinolines.

Some of the esters which may be formed as described, using theappropriate reactants, are:

S-benzoyloxy-Q-ethyl-1,2,3,4-tetrahydroisoquinoline,

S-benzoyloxy-Z-ethyl decahydroisoquinoline,

5-( 3 ,4,5-trimethoxybenzoyloxy)-2-e'thyl-1,2,3,4-tetrahydroisoquinoline,

5 3,4,5 -trimethoxybenzoyloxy) -2-ethyl decahydroisoquinoline,

5 3,4,5 -trimethoxybenzoyloxy) -2-methyl decahydroisoquinoline,

5-( 3,4,5 -triethoxyb enzoyloxy) -2-propyl-1 ,2,3,4-tetrahydroisoquinoline,

5-(p-chlorobenzoyloxy) -2-ethyl-1,2,3,4-tetrahydroisoquinoline, and

5- (o-methylbenzoyloxy) -2-ethyl decahydroisoquinoline.

(Acid addition salts of the bases of this invention are produced bycontacting the compounds with an organic or inorganic acid such ashydrochloric, sulfuric, formic, citric, maleic, succinic and fumaricacids.

Quaternary ammonium salts are formed by contacting the compounds with asuitable alkylating agent such as dimethyl sulfate or an alkyl halidesuch as methyl chloride and ethyl bromide.

The compounds of this invention, being amines, have use as neutralizingagents. In addition, the compounds may be used in the isolation andpurification of penicillin with which they will form salts.

-The compounds of this invention also possess biological activity inanimals and thus are potentially useful as drugs. They can be used asbiologically active standards in evaluating other compounds for similaractivity in animals.

Although there is variation in amount of activity between compounds,some of the compounds provided herewith elevate, while some lower, bloodpressure in animals. In addition, the compounds generally increasearterial blood flow in animals following intr-a-arterial injectionexcept for S-hydroxy-2-ethylisoquinolinium halide (bromide) whichdecreases arterial blood flow. Increased blood flow would appeardesirable in the treatment of peripheral vascular and cerebrovascularinsufiiciency.

The following data summarizes animal tests with compounds of thisinvention:

(A) 5-HYDROXY-2-E'IHYLISOQUINODINIUM BROMIDE (-M-2) In mice it has anacute approximate LD of 63125 mg./kg./i.p.

Following intravenous administration of 5 mg./kg. of M Z to thebilateral vagotomized anesthetized dog, M-2 produced an increase (SO-117 mm. Hg) in arterial 'blood pressure accompanied by a moderateincrease in heart rate while essentially no effects were noted onrespiratory rate.

-M-2 produced slight inhibition of the carotid occlusion pressorresponse.

Intra-arterial administration of M-Z decreased peripheral blood flow inthe anesthetized dog.

M-Z was devoid of antiarrhythmic activity in the mouse(chloroform-induced ventricular fibrillation) 'assay procedure. However,the antiarraythmic activity of quinidine, a well-known antiarrhythmicagent, was found 6 to be potentiated by M-2 in this test. This is shownby the following data:

Compound Dose, mg./kg./i.p. No. Mice Protected/ No. Mice Dosed ED 72(6481) M-2-| Q5. 50+ 56 14/15 50+ 50 8/15 50+45 5/15 1 Q.S. is quinidinesulfate. The data show that the ED for quinidine is about 48 when usedwith M-Z. This is much lower than the ED value of 72 obtained whenquinidine was used alone.

(B) S-HYDROXY-Z-ETHYL-l ,2,3 ,4-TETRAHY- DROISOQUINO-LINE HBr (M-S) (C)5-(3,4,5-TRlM-ETHOXYBENZOYLOXY)-Z-ETHYL- l,2,3,4-TETRAHYDROISOQUINOLINEHBr M-6) In mice it has an acute approximate LD of 250- 500mg./'kg./i.p.

At 5 and 10 mg./kg./i.v. of M-6 in bilateral vagotomized anesthetizeddogs a rise of blood pressure of 13 to 25 mm. Hg was obtained withlittle or no change in heart rate. Intr'a-arten'al administration of M-6increased peripheral blood flow in the anesthetized dog.

(D) 5-HYDROXY-2-ETHYLDECAHYDROISO QUIN- OLINE HYD'ROBROMIDE (M-7) A doseof 10 mg./kg. administered by the intravenous route to the bilateralvagotomized anesthetized dog produced a slight rise (8 to 11 mm. Hg) inarterial blood pressure. lntra-aiterial administration of M-7 producedan increase in peripheral blood flow in the anesthetized dog.

(E) BIS-(Z-ETHYLDECAHYDROISOQUINOLINE) ETHER DIHYDROBROMIDE (M-7a) Adose of 5 to 10 mg./kg. administered by the intravenous route to thebilateral vagotomized anesthetized dog produced slight effect (5 to +10mm. Hg) on 'arterial blood pressure. Intra-arterial administration ofM-7a produced an increase in peripheral blood iiow in the anesthetizeddog.

(F) 5 (3,4,5 TRIMETHOXYBENZOYLOXY) 2- ET HYLDECAHYDROISOQUINOLINE HYDRO-BROMIDE (M-8) A dose of 1 to 5 mg./kg. administered by the intravenousroute to the bilateral vagotomized anesthetized dog produced a slight tomoderate (10 to 37 mm. Hg) decrease in arterial blood pressure.Intra-arterial administration of M-8 produced an increase in peripheralblood flow in the anesthetized dog.

The active agents of this invention can be administered to animals aspure compounds. It is advisable, however, to first combine one or moreof the compounds with a suitable pharmaceutical carrier to attain a moresatisfactory size to dosage relationship.

Pharmaceutical carriers which are liquid or solid can be used. Solidcarriers such as starch, sugar, talc and the like can be used to formpowders. The powders can be used for direct administration or they maybe used to make tablets or fill gelatin capsules. Suitable lubricantslike magnesium stearate, binders such as gelatin, and disintegratingagents like sodium carbonate in combination with citric acid can be usedto form tablets.

Unit dosage forms such as tablets and capsules can contain any suitablepredetermined amount of one or more of the active agents, and may beadministered one or more at a time at regular intervals. Such unitdosage forms, however, should generally contain a concentration of 0.1%to 50% by weight of one or more of the active compounds.

A typical tablet can have the composition:

Mg. -hydroxy-2-ethylisoquinolinium bromide 50 Starch, U.S.P. 57 Lactose,U.S.P. 73 Talc, U.S.P. 9 Stearic acid 6 The oral route of administrationis preferred.

The following examples are presented to illustrate the preparation ofcompounds within the scope of this invention.

Example 1.--5-hydroxy-2-ethylisoquinolinium bromide Forty grams (0.28mole) of S-hydroxyisoquinoline was dissolved in 100 ml. of absoluteethanol and refiuxed for 8 hours on a steam bath with 50% excess ethylbromide (40 g.) (0.37 mole). The ethanol and excess ethyl bromide wasthen evaporated off and the resulting brown solid recrystallized fromethanol to yield 57.47 g. (82%) of light brown needles, M.P. 209.4-210.6 C.

Analysis.-Calcd. for C H NOBr: C, 51.97; H, 4.73; N, 5.51; Br, 31.50.Found: C, 51.77; H, 4.68; N, 5.13; Br, 31.50.

Example 2.5-hydroxy-2-ethyl-1,2,3,4-tetrahydrois0- quinolinehydrobromide Five grams (0.0196 mole) of 5-hydroxy-2-ethylisoquinoliniumbromide was dissolved in 250 ml. of absolute ethanol and hydrogenated(Parr hydrogenation apparatus) over 300 mg. of Adams platinum oxide at40 lbs. per sq. in. pressure at room temperature. A white crystallinesolid separated when the hydrogenation was terminated (5 hrs.). Thehydrogenated suspension was heated on a steam bath until theprecipitated solid had redissolved; the exhausted catalyst was thenfiltered off. The filtrate was concentrated, from which 4.5 g. (90%) ofcolorless plates crystallized on cooling, M.P. 223.8- 224.6 C. Theultraviolet spectrum of this compound had k 272 and 277 my (log 6 3.24and 3.25, respectively.).

Analysis.-Calcd. for C H NOBr: C, 51.17; H, 6.20; N, 5.43; Br, 31.01.Found: C, 51.17; H, 6.06; N, 5.42; Br, 31.28.

Example 3.-5-(3,4,S-trimethoxybenzoyloxy)-2-ethyl-1,2,3,4-tetrahydroisoquinoline hydrobromide Four and three-tenths grams(0.0166 mole) of S-hydroxy 2-ethyl-1,2,3,4-tetrahydroisoquinolinehydrobromide was dissolved in 100 ml. of water and sodium hy droxidesolution added until no further precipitation was evident. The resultingsuspension was extracted with ether, dried, and the solvent removed toyield 3.0 g. (100%) of white solid. This base was dissolved in 100 ml.of dry benzene and added to a solution of 4.0 g. (0.0173 mole) of3,4,5-trimethoxybenzoyl chloride in 100 ml. of dry benzene. Two grams ofdry sodium bicarbonate was added to this mixture and the whole refluxedfor 8 hours on a steam bath. The gelatinous precipitate which separatedout was filtered (3.3 g.) and the filtrate extracted with dilutehydrochloric acid. This acid extract, made alkaline with sodiumhydroxide, was extracted with ether and dried. The ether was removed toyield 3.6 g. of a pale yellow oil. The hydrobromide 8 salt of this basewas recrystallized from ethanol-ether to yield 3.7 g. (32.3%) as shortwhite needles, M.P. 213.2213.4 C.

Analysis.-Calcd. for C H NO Br: C, 55.75; H, 5.75; N, 3.10; Br, 17.70.Found: C, 55.59; H, 5.71; N, 3.18; Br, 17.80.

Example 4.--5-hydroxydecahydroisoquinoline and hydrochloride Five gramsof S-hydroxyisoquinoline was dissolved in 50 ml. of glacial acetic acidand 0.5 ml. of concentrated sulfuric acid added. The resulting solutionwas hydrogenated over 5 g. of Adams platinum oxide at 50 lbs. per sq.in. pressure for 36 hours at room temperature. The exhausted catalystwas filtered from the hydrogenated solution and the filtrate dilutedwith approximately 50 ml. of water, made alkaline by the addition ofsodium hydroxide pellets, and extracted with ether. The dried etherealextract was evaporated carefully to yield a yellow oily residue (2.7 g.)which was treated with dry hydrogen chloride in ether to yield 2.9 g.(51%) of the base hydrochloride, recrystallized from ethanol-ether, M.P.191:0-1930" C. The ultraviolet spectrum of this compound was taken inwater and showed no absorption throughout the range 220-340 mg.

Analysis.Calcd. for CgHmNOCiZ C, 56.25; H, 9.38; N, 7.29; Cl, 18.75.Found: C, 56.33; H, 9.43; N, 7.22; Cl, 18.80.

Example 5.-5-hydroxy-2-ethyldecahydroisoquinoline and hydrobromide Eightgrams (0.031 mole) of 5-hydroxy-2-ethylisoqinolinium bromide was treatedwith moist silver oxide, prepared from the action of sodium hydroxide onsilver nitrate (13 g.), in ml. of a 50% aqueous methanol solution for 24hours. The silver bromide formed was then filtered from the solutionusing celite/ charcoal mixture as a filter aid. The solvent wasevaporated off under reduced pressure at as low a temperature aspossible to yield 5.7 g. (96%) of 5-hydroxy-2-ethylisoquinoliniumhydroxide. This compound was hydrogenated as described in Example 4. Theresulting 5-hydroxy-2-ethyldecahydroisoquinoline was converted to thehydrobromide 5.62 g. (81%), which was recrystallized from ethanol-etherto yield fine white needles, M.P. 218.42l9.0 C. The ultraviolet spectrumof this compound indicated no absorption in the range 220-310 mp.

Analysis.--Calcd. for C H NOBr: C, 50.00; H, 8.33; N, 5.30; Br, 30.31.Found: C, 49.80; H, 8.31; N, 5.52; Br, 30.38.

Example 6.5-(3,4,5-trimethoxybenzoyloxy)-2-ethyldecahydroisoquinolineand hydrobromide Five grams (0.027 mole) of5-hydroxy-2-ethyldecahydroisoquinoline was dissolved in 20 ml. of sodiumdried toluene and added to a solution of 15 g. (0.065 mole) of3,4,5-trimethoxybenzoyl chloride and refluxed for 48 hours. Theresulting suspension was filtered and the toluene filtrate extractedwith dilute hydrochloric acid. Neutralization of this acid extract wasfollowed by ext-raction with ether. The ether extract was dried andevaporated to yield a brown viscous oil. This was purified bychromatography on a Florosil column and eluted with petroleum ether(6090 C.)-ether (10:1). Large prisms separated from the fractions onstanding overnight. This material was crystallized from petroleum ether(30-60 C.) to yield 4.52 g. (52%) of large prisms, M.P. 99.8-100.3 C.

Analysis.Calcd. for C H NO C, 66.82; H, 8.28; N, 3.71. Found: C, 67.06;H, 8.32; N, 3.64.

One gram of the base was converted to the hydrobromide andrecrystallized from ethanol-ether to yield 1.06 g. (88%) of short whiteneedles, M.P. 1973;- 198.6 C.

9 A/zal v.s'i.s'.-Calcd. for C H NO Br: C, 55.02; H, 7.04; N, 3.06; Br,17.43. Found: C, 55.12; H, 7.15; N, 3.11; Br, 17.50.

Example 7.-Bis- 2-ethyldecahydroisoquinoline) ether Five grams of5-hydroxy-2-ethylisoquinolinium bromide was dissolved in 50 ml. ofglacial acetic acid with the aid of gentle heating on a steam bath.Five-tenths ml. of concentrated sulfuric acid was added and the mixturehydrogenated over 5 g. of Adams platinum oxide at 50 lbs. per sq. in.pressure for a period of 36 hours at room temperature. The exhaustedcatalyst Was filtered, the acidic filtrate diluted with water and madestrongly alkaline by the addition of sodium hydroxide solution. The basewas then extracted with ether and converted to the hydrobromide salt.Upon recrystallization from ethanol-ether, 2.14 g. (42%) of fine Whiteneedles were obtained, melting at 196.6197.1 C. The ultraviolet spectrumof this compound showed no absorption through the range 220-310 m Theinfrared spectrum (KBr) showed a medium absorption band at 1110 cm.- inaccordance with the absorption reported for an ether linkage in L. J.Bellamy, The Infrared Spectra of Complex Molecules, Wiley and Sons, NewYork, 1958, p. 115.

Analysis.Calcd. for C H N OBr: C, 52.52; H, 8.29; N, 5.49; Br, 31.31.Found: C, 52.57; H, 8.48; N, 5.41; Br, 31.20.

Example 8.Diethiodide of bis-(Z-ethyldecahydroisoquinoline) ether Thediethiodide derivative of the basic ether of Example 7 was prepared byrefluxing the free base, obtained from the neutralization of 1.0 g. ofbis-(2-ethyldecal1ydroisoquinoline)ether dihydrobromide, dissolved in 25ml. of dry benzene, for 4 hours with excess ethyl iodide. Theprecipitated quaternary iodide was filtered and recrystallized from analcohol-ether mixture to yield 0.93 g. (72%) of fine white needles, M.P.245.0-245.4 C. The infrared spectrum (KBr) showed a medium intensityabsorption band at 1110 cm.-

Analysis.Calcd. for C H N OI C, 47.28; H, 7.63; N, 4.24; I, 38.43.Found: c, 47.28; H, 7.40; N, 4.27; I, 38.20.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. A compound of the formula no I and acid addition salts thereof.

2. '5-hydroxy decahydroisoquinoline.

3. S-hydroxy decahydroisoquinoline hydrohalide.

4. The process which comprises reducing a compound 10 by catalytichydrogenation using a platinum oxide catalyst and glacial acetic acid asthe reaction medium to produce a compound of the formula 5. The processwhich comprises reducing a compound of the formula by catalytichydrogenation using a platinum oxide catalyst and glacial acetic acid asthe reaction medium to produce a compound of the formula ReferencesCited UNITED STATES PATENTS 2,395,526 2/11946 Woodward et al. 260289 X8,015,661 "M1962 Georgian 260 2;89 X 13,022,308 2/ 1962 Cavallito et al.260286 8,317,541 5/1967 Umezawa et al. 2-60-289 X OTHER REFERENCESKimoto et al.: Chem. Pharm. Bull. (Japan), vol. 9, pp. 480 84 (1961).

Witkop: J. Am. Chem. Soc., vol. 70, pp. 2617-9 (1948) ALEX 'MAZEL,Primary Examiner.

D. G. DAUS, Assistant Examiner.

